The metallothioneins provide a useful model to study how eukaryotic genes are regulated and how the gene products allow cellular adaptation and homeostasis. Using the simple unicellular eukaryote Saccharomyces cerevisiae, a detailed analysis of the cis-acting control sequences that regulate metallothionein gene transcription in response to copper has been carried out. In addition, a trans- acting gene required for transcriptional induction has been identified and cloned. We propose that regulation of the yeast gene occurs through the interaction of both positive and negative factors. Structure-function relationships of yeast metallothionein have been studied by a combination of site-specific mutagenesis and biophysical techniques and residues critical to the functional activity of this protein have been identified. Metallothionein gene regulation in the more complex cells of the mouse has also been analyzed. Systematic point mutagenesis of the control region reveals different residues required for induction and for efficient transcription. Two factors that bind to these regions have been identified and separated.